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2021 Merkin Center Research Grant Recipients

The Merkin Peripheral Neuropathy and Nerve Regeneration Center is proud to announce its inaugural grants, awarded to 10 researchers across Johns Hopkins. Learn more about the recipients and their work below:

Sarah Berth

Sarah Berth, M.D., Ph.D.

Neurologist, Johns Hopkins Medicine

Topic: Genetic Screen for Axonal Degeneration Modifiers

  • Sarah Berth, M.D., Ph.D., is a neurologist with expertise in neuromuscular disorders She specializes in neuromuscular medicine, motor neuron diseases and muscle diseases.

    Dr. Berth earned her M.D. and Ph.D. from the University of Illinois-Chicago. She then came to The Johns Hopkins Hospital for her neurology residency, where she also completed a fellowship in neuromuscular medicine. 

    Dr. Berth’s research interests include understanding cellular mechanisms for degeneration in neuromuscular disease.  She is particularly interested in understanding how transport of organelles and autophagy (clearance of damaged proteins) is disrupted in amyotrophic lateral sclerosis (ALS).

    More About Dr. Berth

  • The objectives of this project are to use Drosophila models to identify novel therapeutic targets for peripheral neuropathy. Furthermore, we will study the mechanisms of axonal transport disruption in multiple fly models of CMT.

    Our activities will include a genetic screen to identify novel regulators of axonal degeneration in both flies and primary rat DRG neurons, primary culture and use of compartmentalized microfluidic devices in primary rat DRG neurons, and live cell imaging of axonal transport.

    Our strategies will be to start with an unbiased, forward genetic screen to define new genetic targets to assess their impact on axonal degeneration, after which we will comprehensively evaluate these targets to validate them.

    We will also fully characterize axonal transport defects in TRPV4, GARS and mitofusin mutant models to determine if there is targeted or global axonal transport disruption.

Aysel Fisgin

 

Aysel Fisgin, Ph.D.

Post-Doctoral Research Fellow, Johns Hopkins University

Topic: MAP4K4 Inhibition to Prevent CIPN

  • Aysel Fisgin, Ph.D., received her BS degree in Chemical Engineering at Middle East Technical University, Turkey, in 1993. After 15 years of working as a professional in industry, then starting up and managing her own business, she started graduate school and got her MS degree in Medical Systems and Informatics from Bogazici University, Turkey.

    She pursued her Ph.D. in Biomedical Engineering at Bogazici University in Turkey till she moved to the US in 2013. She received a European Union Marie Curie Actions IRSES Project scholarship and carried out her Ph.D. thesis experiments in Biomedical Engineering, Johns Hopkins. Her Ph.D. thesis research is on high throughput drug screening against CIPN (Chemotherapy-Induced Peripheral Neuropathies).

    She is currently a post-doctoral research fellow in Hoke Lab, Neurology, Johns Hopkins University. She works on in-vitro and in-vivo peripheral neuropathy models of different chemotherapy drugs and transgenic mice that are resistant to the development of neuropathies caused by these chemotherapy agents.

    Her research focus is on identifying therapeutic drugs that can be co- or pre-administered to cancer patients with chemotherapy agents before axonal degeneration starts.

  • There are currently no effective therapies that ameliorate CIPN, which may prevent patients from receiving the most effective treatment for their cancer. Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and diseases, including diabetes, cancer, inflammation, and angiogenesis. MAP4K4 and its downstream targets are also involved in neurodegeneration. Inhibition of MAP4K4 extended the survival of motor neurons collected from mice and patients with amyotrophic lateral sclerosis (ALS) and treatment with MAP4K4 inhibitors was sufficient to attenuate axonal degeneration and neuronal apoptosis in DRG neurons.

    A MAP4K4 inhibitor, PF-06260933 dihydrochloride, provided robust protection against neurotoxicity of Paclitaxel (PTX), Cisplatin (CDDP) and Bortezomib (BTZ) in-vitro. With these findings, that axon degeneration cascades initiated by PTX, CDDP, and BTZ may converge on MAP4K4 and that inhibitors of MAP4K4 can be used to prevent neurotoxicity of different chemotherapy drugs.

    In this project, I am planning to validate in-vitro neuroprotective effect of PF-06260933 dihydrochloride with three chemotherapeutic drugs and also validate whether the neuroprotective effect of PF-06260933 dihydrochloride is an off-target effect or directly related to MAP4K4.

    Furthermore, I will examine the effect of MAP4K4 inhibition in an in-vivo model of PTX induced Peripheral Neuropathy and whether MAP4K4 inhibition has any effect on Paclitaxel’s ability to kill cancer cells. 

Sang-Min Jeon

Sang-Min Jeon, Ph.D.

Research Associate, Johns Hopkins University

Topic: Sprouting Mediated Skin Reinnervation

  • Dr. Sang-Min Jeon received his bachelor's degree in the department of biology from Yeungnam University in Korea in 2005 and obtained both master's and doctorate degree in 2008 and 2011 from the department of anatomy in the school of medicine, Kyungbook National University, in Korea.

    While in graduate school, he made multiple key discoveries regarding the interplay between immune cells, cytokines, and sensory neurons in the dorsal root ganglion and spinal cord in the setting of chronic pain, including neuropathic pain.

    In 2013, he came to Johns Hopkins University as a postdoctoral fellow in the laboratory of Dr. Michael Caterina, MD., Ph.D., in the Department of Biological Chemistry. During his postdoctoral fellowship, he carried out the most extensive anatomical analysis to date of the distribution of Merkel cells in the various territories of the mouse hind paw. These anatomical studies provided a vivid picture of the Merkel cells and their associated afferent neurons, as well as changes in these cells following nerve injury. He has also focused on experiments to determine whether the RNA binding proteins Lin28a and Lin28b, which regulate the biogenesis of let-7 family miRNA, participate in neuropathic pain.

    After completion of his fellowship, he was recruited as a research associate in the Department of Neurosurgery and the Neurosurgery Pain Research Institute in 2018 and was promoted to an instructor in 2021. During this time, he has been studying how immune cells in the skin contribute to sprouting after peripheral nerve injury and sprouting mediated sensory recovery.

  • Peripheral nerve injury results not only in loss of motor function, but also in loss of sensory functions needed to mediate protective reflexes and tactile acuity, and in the development of unwanted symptoms such as neuropathic pain.

    Functional recovery following nerve injury can occur through two distinct processes: axon regeneration in injured neurons and/or collateral sprouting of nearby uninjured neurons. Because recovery through axon regeneration can be extremely slow, and in some cases fails, enhancement of collateral sprouting-based reinnervation might augment functional sensory recovery after nerve injury. Immune cells are recruited to the site of nerve damage and play a pivotal role in the phagocytic clearance of nerve cells and myelin debris.

    While much has been learned about the contributions of immune cells to neural recovery through axon regeneration, relatively less is known regarding their function in restoring sensory function to skin through collateral sprouting.

    Therefore, our goal in this study is to determine whether immune cells contribute to sprouting after peripheral nerve injury. 1) To identify and characterize changes in the abundance, activation state, and localization of immune cell types in denervated skin after peripheral nerve injury and during collateral reinnervation, using immunohistochemistry and flow cytometry. 2) To determine the necessity of specific immune cell populations for collateral sprouting mediated reinnervation, by examining sprouting mediated skin reinnervation and sensory recovery in mice in which individual immune cell types have been depleted.

Dr. Ying Liu

Ying Liu, M.D., Ph.D.

Assistant Professor, Johns Hopkins University

Topic: Evaluating the effect of SARM1 deficiency on peripheral neuropathy in db/db mouse model of type 2 diabetes.

  • Ying Liu, M.D., Ph.D., received her medical degree in China and Ph.D. degree in Japan. She finished her postdoctoral fellow training in the Division of Neuropathology in the Johns Hopkins University School of Medicine. Now as an assistant professor in the Cutaneous Nerve Laboratory of Neurology at Johns Hopkins, her focus is on evaluation of autonomic nerve fiber densities in skin biopsies for clinical diagnosis of autonomic neuropathy.

    Her expertise includes investigating the risk factors influencing autonomic fiber degeneration in human and experimental animal models. Dr. Liu's continuing work seeks to deepen the understanding of neuropathy mechanisms using genetic model systems. Her studies involve developing the biomarker for cardiac autonomic neuropathy and age-related neurodegenerative diseases and studying the potential therapeutic strategy for diabetic neuropathy as well as chemotherapy induced neuropathy.

    Dr. Liu's current research efforts include diabetic autonomic neuropathy, cardiac autonomic neuropathy and chemotherapy-induced autonomic neuropathy. Specific projects include combined analysis of autonomic neuropathy and sweat function test in diabetic transgenic animal models and chemotherapy-induced neuropathy animal models and evaluation the mechanism of fiber degeneration and regeneration in neurodegenerative disease.

  • Peripheral neuropathy in diabetic patients predominantly affects sensory and autonomic nerves. Sensory neuropathy is associated with neuropathic pain, sensory loss, while autonomic neuropathy is rarely studied and is particularly important because of its involvement in multiple internal organs, invisible onset, and serious impact on quality of life, which includes sudden cardiac death, abnormal sweating, sexual dysfunction, and gastrointestinal dyskinesia.

    Diabetic neuropathy is chronic and progressive. Despite the large clinical impact, preventing or slowing progression of diabetic neuropathy remains an unmet need. The pathogenesis of diabetic peripheral neuropathy (DPN) is incompletely understood though several mechanisms have been proposed including mitochondrial dysfunction and SARM1 activation. The activation of SARM1 may lead to the enzymatic destruction of NAD+ and the subsequent degeneration of axons. SARM1 activation in axons is usually inhibited by NMNAT2. The previous study has shown that mitochondrial impairment may trigger SARM1 activation to lead axon degeneration. Multiple laboratories, as well as our own data, have shown that mtDNA deletion plays a role in diabetic neuropathy.

    Therefore, in this proposal, we will assess the effect of SARM1 inhibition through genetic knockdown in the type II diabetes model, the db/db mouse. We have established the ability to breed db/db / SARM -/- animals and will focus on sensory and autonomic assessments using unbiased methodologies and will determine if SARM1 inhibition leads to improved mitochondrial function and performance. Our proposal is of great significance for understanding the pathological mechanism of diabetic neuropathy, and may bring new treatment methods to painful neuropathy.

Brett McCray

Brett McCray, M.D., Ph.D.

Neurologist, Johns Hopkins Medicine

Topic: TRVP4 in Nerve Injury

  • Dr. Brett McCray is a neuromuscular neurologist physician-scientist with a clinical and research focus on peripheral neuropathy.

    After obtaining M.D., Ph.D. training at the University of Pennsylvania, he completed neurology residency in the Mass General Brigham Neurology program. He then completed a neuromuscular neurology fellowship at Johns Hopkins where he is currently an assistant professor in neurology.

    His primary focus is on Charcot-Marie-Tooth (CMT) disease, the most common form of inherited neuropathy and the most common inherited neurologic disease worldwide. In addition to caring for patients with CMT, peripheral neuropathy, and other neuromuscular diseases, he has a basic science lab focused on the study of inherited forms of peripheral neuropathy with the goal of identifying common pathogenic mechanisms and novel broadly applicable therapeutic targets.

    His current work is focused on understanding the pathogenesis of CMT type 2C, which is caused by mutations in the calcium-permeable cation channel TRPV4 (transient receptor potential vanilloid 4). His laboratory research uses a combined strategy of analyzing cultured cells as well as fly and mouse models of nerve disease to understand pathways important in the development of neuropathy.

    Their work has demonstrated that drugs that inhibit the activity of TRPV4 could potentially have therapeutic applications not only for patients with CMT2c but in other situations in which nerves are injured.

    More About Dr. McCray

  • The ion channel TRPV4 is emerging as contributor to pathogenesis in a broad range of neurological disorders. Dominant missense mutations in TRPV4 cause various forms of neuropathy, and increased TRPV4 activation has been implicated in a range of nerve injury paradigms, including traumatic brain injury (TBI), stroke, spinal cord injury, and toxic peripheral neuropathy.

    However, the specific mechanisms by which TRPV4 may impact pathology in these conditions is unclear. Our preliminary work using a recently generated knockin mouse model of TRPV4 neuropathy has revealed an unexpected role for TRPV4 in regulating blood-neural-barrier (BNB) integrity.

    As disruption of the BNB is increasingly recognized as an important pathological process underlying nerve injury in a variety of neurological conditions, these results suggest that existing orally bioavailable TRPV4 antagonists could be hold promise for a range of currently untreatable neurological insults. In this proposal, we will test the role of TRPV4 activity in a well-characterized mouse sciatic nerve crush model of peripheral nerve injury and regeneration.

    We will determine the expression pattern of TRPV4 in different cell types in peripheral nerve and test how activation or inhibition of TRPV4 affects multiple aspects of nerve damage and regeneration.

Kathryn Moss

Kathryn Moss, Ph.D.

Post-Doctoral Fellow, Johns Hopkins University

Topic: Development of a CMT1A/CIPN Mouse Model

  • Dr. Kathryn Moss received her BS degree in Cellular and Molecular Biology from the University of Michigan and her Ph.D. in Biochemistry, Cell and Developmental Biology from Emory University. She completed her dissertation with Dr. Gary Bassell studying posttranscriptional mechanisms required for neuronal development and function.

    Dr. Moss is currently a postdoctoral fellow in the laboratory of Dr. Ahmet Höke at Johns Hopkins University School of Medicine. Her research interests are focused on understanding the pathogenesis of Charcot-Marie-Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

    Remarkably, these demyelinating peripheral neuropathies are caused by altered dosage of the same gene; the Peripheral Myelin Protein 22 (PMP22) gene is heterozygously duplicated in CMT1A and heterozygously deleted in HNPP. Although CMT1A and HNPP are the most common inherited peripheral neuropathies, no disease-modifying treatments are currently available.

    Therefore, Dr. Moss is working to develop improved mouse models of CMT1A and HNPP. These models will facilitate candidate therapy evaluation and provide insight into the physiological function of PMP22 and how altered gene dosage impacts this function.

    Dr. Moss’ research endeavors are enhanced by her involvement in the Peripheral Nerve Society. She serves as Chair of the Junior Committee and as a member of several other committees.

  • Charcot-Marie-Tooth Disease Type 1A (CMT1A) is the most common inherited peripheral neuropathy and even though this disease dramatically affects patient quality of life and burdens the healthcare system, there are currently no disease-modifying treatments. CMT1A is caused by duplication of Peripheral Myelin Protein 22 (PMP22), a Schwann-cell enriched gene. Although CMT1A pathogenesis initially occurs in myelinating Schwann cells, secondary axon degeneration has been suggested to drive functional deficits in patients.

    Unfortunately, current CMT1A mouse models poorly recapitulate the secondary axon degeneration observed in patients necessitating the development of improved mouse models.

    Axon degeneration occurs in Chemotherapy Induced Peripheral Neuropathy (CIPN) patients and mouse models and chemotherapy treatment has been demonstrated to exacerbate CMT1A patient symptoms. Therefore, I intend to develop a combined CMT1A/CIPN mouse model to enhance secondary axon degeneration.

    The therapeutic efficacy of inhibiting the programmed axonal degeneration pathway will then be evaluated in this CMT1A/CIPN model by knocking out the central executioner of this pathway, SARM1. Results from these studies will lead to an improved CMT1A mouse model that more closely resembles patients which is required to facilitate therapeutic discoveries for this disease. 

Bipisha Mukherjee Clavin

Bipasha Mukherjee-Clavin, M.D., Ph.D.

Neuromuscular Fellow, Johns Hopkins Medicine

Topic: KIF16B-CMT2

  • Dr. Bipasha Mukherjee-Clavin is currently a Neuromuscular fellow in the Neurology Department in the Johns Hopkins University School of Medicine. She was previously an M.D./Ph.D. student in the Medical Scientist Training Program at Johns Hopkins University, during which she earned a Ph.D. in Neuroscience under the mentorship of Dr. Gabsang Lee.

    As part of her dissertation, she modeled Charcot Marie Tooth 1A, a genetic Schwann cell disorder, with three different patient-derived Schwann Cell models: human induced pluripotent stem cells, human embryonic stem cells, and direct lineage converted cells. During her Neurology residency, she received the NINDS R25 award to support an ongoing project in the laboratory of Dr. Ahmet Hoke investigating the relationship between CMT2 and the kinesin KIF16B, a variant of uncertain significance found through whole exome sequencing of two brothers with CMT2. This project won the Jay Slotkin award, given annually to a graduating Johns Hopkins neurology resident for excellence in neurological research.

    She is pursuing clinical and basic science training in Neuromuscular disorders with the goal of developing a translational and precision medicine program using patient-derived engineered cells to better understand and alleviate peripheral neuropathies.

  • We have identified a patient and his brother with late onset inherited axonal neuropathy, Charcot-Marie Tooth type 2 (CMT 2), in whom whole exome sequencing revealed two variants of uncertain significance in the kinesin gene KIF16B, which has never previously been reported to be a cause of neuropathy. KIF16B facilitates early endosomal trafficking, and the mechanism through which it may cause axonal neuropathy merits investigation.

    The purpose of this study is to better determine the link between the KIF16B mutations and CMT2, through the use of patient-derived induced pluripotent stem cell-derived neurons and drosophila models.

    Though these studies, we hope to develop novel insight into the role that aberrant early endosomal trafficking may play in the development of late onset axonal neuropathy.

Dr. Seong-Hyun Park

Seong-Hyun Park, Ph.D.

Post-Doctoral Research Fellow, Johns Hopkins University

Topic: CMT PNSorganoid Model

  • Dr. Seong-Hyun Park received bachelor's degree in chemistry in 2011 and Ph.D. in chemical biology in 2018 from Yonsei University in South Korea.

    During his Ph.D., he built his career in the field of cancer research and chemical biology based on chemical tools and compounds (e.g., high-throughput screening (HTPS) for drug discovery, the discovery of new biological processes using artificial ion transporters and/or artificial receptors, the development of a new platform for investigating cellular mechanisms and the development of molecular probes for detection of pathogen and/or cellular enzymes) in a chemical biology laboratory.

    His major findings and results were: i) the identification of new biological functions and processes (e.g., apoptosis and autophagy in cancer) via screening with known or unknown biofunctional chemicals (e.g., synthetic ion transporters, synthetic receptors, hybrid molecules with anti-cancer and anti-leukemia agents), ii) the suggestion of a new platform for investigation of biological processes, iii) the discovery of new anticancer agents using fluorescent polarization (FP) based HTPS.

    In 2019, he joined the Gabsang Lee Lab as a postdoc fellow to expand his expertise in the field of stem cells. His plan focuses on Schwann cell biology and pathology to develop a hiPSC-based platform for a high throughput screening, a new humanized and patient-specific myelination 3D PNSorganoid model of Charcot-Marie-Tooth (CMT) diseases, and a new strategy to isolate competent human Schwann cells for pharmacological rescue and cell replacement therapy in future.

  • Modelling peripheral neuropathy to develop new therapeutic strategies is highly challenging. One of the most common peripheral neuropathies is Charcot-Marie-Tooth (CMT) diseases that disrupt myelin structures, leading to permanent neuron loss, significant pain, and morbidity with life-long debilitating symptoms. The current in vitro and rodent of CMT have provided valuable information, but there is no effective treatment, partly because of a lack of human Schwann cell model with robust myelination capacity.

    A three-dimensional (3D) organoid technology derived from human embryonic stem cells (hESCs) and human induced pluripotent cells (hiPSCs) has revolutionized current stem cell-based disease modeling and translational adoption in drug screening and regenerative medicine. However, to date there are no studies or reports on CMT disease modeling using organoid model. To address these limitations, we propose to utilize our established 3D PNSorganoid model to study CMT diseases.

    In this proposal, we will model CMT1A and 1X with our PNSorganoid model. The CMT hiPSC lines, along with healthy control and isogenic control hiPSC lines, will be differentiated into PNSorganoids, using our established protocol, followed by molecular and cellular phenotyping, with focusing on Schwann cell populations.

    In conclusion, our PNSorganoid containing myelinating Schwann cells interconnected with peripheral neurons will be generated from CMT hiPSCs, followed by detailed molecular and cellular analyses. Our “CMT PNSorganoid” model will be beneficial for uncovering disease mechanism in human Schwann cells, and also lead us to develop a new strategy for developing better therapeutic drugs and cell replacement therapies in near future.

Sami Tuffaha

Sami Tuffaha, M.D.

Plastic Surgeon, Johns Hopkins Medicine

Topic: Gene Expression Changes with Schwann Cell Denervation

  • Sami Tuffaha is an Assistant Professor of Plastic Surgery, Neurosurgery, and Orthopedic Surgery at Johns Hopkins University School of Medicine. He received his integrated plastic surgery residency training at Johns Hopkins/University of Maryland and then completed a hand surgery fellowship at Mayo Clinic with an emphasis on brachial plexus repair and microsurgery. His clinical practice is largely focused on peripheral nerve surgery and functional reconstructive microsurgery.

    He leads a basic and translational research program aimed at developing novel therapeutics, devices and surgical approaches to improve functional recovery and prevent neuropathic pain following nerve injury, with ongoing clinical trials arising from work performed in the lab.

    He is also studying the mechanisms and timing of denervation-induced muscle and Schwann cell atrophy that manifest in diminished functional recovery following delayed repair of nerve injuries.

    More About Dr. Tuffaha

  • Functional recovery following surgical repair of peripheral nerve injuries tends to be poor in the setting of proximal nerve injury or delayed repair. This is due to the deleterious effects of chronic denervation on the target muscle and the Schwann cells in the distal nerve track. Throughout the latent period between nerve injury and surgical repair as well as the lengthy period of time required for axonal regeneration to occur, the Schwann cells in the distal nerve lacking axonal interaction progressively lose their capacity to proliferate and provide critical trophic support to the regenerating axons.

    A number of genes have been implicated in this process. However, studies are lacking that take into account both mRNA and protein expression. Furthermore, the critical gene expression changes and timing of those changes with progressive Schwann cell denervation has been studied almost exclusively in rodent models, leaving unanswered questions regarding how these temporal changes in gene expression compare to those in humans.

    To address these critical knowledge gaps, we will first evaluate the functionally significant changes in Schwann cell gene expression that occur with progressive denervation in a rat model in which the sciatic nerve is transected and left in discontinuity for varying periods of time. The denervated nerve tissue will be analyzed with RNA-sequencing followed by proteomics analysis to confirm the validity and functional significance of the critical gene expression changes that are identified. The same analysis will also be performed on denervated nerve tissue collected from patients undergoing nerve repair with varying durations of delay from time of injury to time of surgery. In doing so, we will gain new understanding of the critical genes expression changes that occur in humans.

    By comparing the gene expression profiles in humans and rats, we will seek to establish correlations that will facilitate more meaningful interpretation of findings from future studies in rat models.

Eric Villalón Landeros

Dr. Eric Villalón Landeros

Post-Doctoral Fellow, Johns Hopkins University

Topic: DRG Neuroproteasome Signaling Peptides

  • Dr. Eric Villalón Landeros is a postdoctoral fellow in the laboratory of Dr. Seth S. Margolis in the department of Biological Chemistry at The Johns Hopkins University School of Medicine. Originally from Guanajuato, Mexico, Dr. Villalón Landeros received his B.S. in Neurobiology, Physiology, and Behavior from the University of California-Davis.

    Dr. Villalón Landeros obtained his Ph.D. in Biological Sciences with an emphasis in Neurobiology from the University of Missouri in 2016. During his Ph.D., Dr. Villalón Landeros used cellular, molecular, and behavioral approaches to investigate the mechanisms of peripheral nerve pathology in mouse models of Charcot-Marie-Tooth type 2E.

    After his Ph.D., Dr. Villalón Landeros was a postdoctoral fellow in the laboratory of Dr. Christian Lorson in the Veterinary Pathobiology department at the University of Missouri. During this postdoc, Dr. Villalón Landeros investigated peripheral nerve pathology in Spinal Muscular Atrophy (SMA) and SMA with Respiratory Distress type I with the aim of discovering and developing viral-mediated therapeutics for the treatment of these diseases.

    Following extensive publications in the area of peripheral nerve pathology Dr. Villalón Landeros decided to join efforts with Dr. Seth S. Margolis with the desire to build on his expertise in the area of biochemical and mechanistic studies in the mammalian nervous system. Through this effort, Dr. Villalón Landeros has made new discoveries related to protein degradation and built the foundation of a research program investigating these mechanisms within the periphery that has potential significant relevance to development and function of the peripheral nervous system in health and disease.

  • Proper function of the peripheral nervous system is dependent on functional proteasomes. Indeed, treatment of human patients with proteasome inhibitors, such as Velcade for multiple myeloma, results in painful neuropathies. The exact mechanisms resulting in development of these neuropathies are not well understood and suggest an unmet need in understanding proteasomes in PNS biology.

    Our discovery of the neuronal membrane proteasome (NMP) in DRG neurons that can regulate neuronal activity via extracellular signaling peptides, suggests a potential role for proteasomes in the PNS that has not previously been described.

    Our hypothesis is that in DRG neurons the NMP produces peptides that bind receptors on specific neurons to modulate their sensitivity to stimuli. The aim of this proposal is to identify the specific NMP released signaling peptides involved in modulating sensory neuron activity.

    To do this we will utilize our laboratories developed proteomic approaches to isolate, purify, and identify specific NMP released peptides and study how these peptides regulate critical functions of the PNS sensory neurons.

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